PROJECT SUMMARY Multiple myeloma (MM) is an incurable plasma cell malignancy with a 50% survival rate. MM is the leading hematological cancer in African Americans, who are diagnosed 2-3 times more commonly than whites. The factors contributing to this disparity remain unclear, but genetics and immune dysregulation are believed to play a key role. The scientific goals of this proposal are: (1) to apply integrative and innovative methods that leverage genetic and transcriptomic data to elucidate biological pathways contributing to this disparity and (2) to contribute evidence to inform future precision health efforts in this population. The first objective will be to identify putative causal genes associated with MM susceptibility by conducting a transcriptome-wide association study (TWAS), using genetic prediction models of gene expression developed specifically in African Americans. TWAS will be performed by imputing gene expression profiles in 1813 cases from the African American Multiple Myeloma Study (AAMMS) and 8871 controls, the largest genome-wide association study of MM in African Americans. The next objective will focus on white blood cell (WBC) traits, which are important intermediate phenotypes for hematologic and immune-related cancers. The distribution and genetic architecture of WBC traits varies substantially across ethnicities and may contribute important information for deciphering MM risk in African Americans. The shared genetic basis of WBC variation and MM susceptibility will be examined by conducting: (1) genome-wide genetic correlation analyses and (2) developing genetic scores for predicting an individual?s inherited predisposition to a specific WBC profile. Genetic scores will be applied to AAMMS data to test their association with MM, and comparative analyses of WBC-predictors from African and European ancestry populations will be conducted. The last research component will aim to elucidate genetic factors that are associated with specific features of MM tumors. Analyses will focus on examining the contribution of local genetic ancestry to somatic events, such as translocations and amplifications that are more commonly observed in African American patients. The role of genetic mechanisms involved in gene expression or alternative splicing will also be investigated, to test the hypothesis that some tumor features seen in African Americans are due to germline genetic effects on these processes. This research plan is complemented by a training plan that builds on the applicant?s strengths in cancer and genetic epidemiology to develop new expertise in integrative and ancestry-aware genomic analyses, hematological cancer, and cancer disparities. Novel insights into MM etiology in African Americans will be important for improving health outcomes in this population that is disproportionately affected by MM, yet under- represented in genetics studies. The research and training plan will prepare the applicant for a successful independent career in cancer research with an interdisciplinary focus on risk stratification and cancer control.